Metabolic Surgery for Steato-Hepatitis

NCT04282005 | Unknown

• 1 other identifier: 267076
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes mellitus (T2DM) and is characterised by excess liver fat on imaging or histology. NAFLD affects up to 25% of the Western population. It's more aggressive form is non-alcoholic steatohepatitis (NASH) characterised by cell injury, inflammation and fibrosis, and is associated with increased mortality from liver and cardiovascular disease. Currently, there is no specific treatment for NASH. Diet and exercise-induced weight loss remain the only recommended options. However, maintaining weight loss in the long term is difficult. There is therefore a significant unmet need for effective therapy in patients with NASH that can address the underlying mechanisms of disease. Although preliminary observational evidence suggests that bariatric/metabolic surgery, especially RYGB can improve NASH, no controlled trials to date has confirmed the efficacy of surgery compared to standard weight loss programs. Also, while animal and clinical studies have shown that bariatric surgery exerts weight-independent effects on glucose metabolism, it is yet unknown if the observed effects of bariatric/metabolic surgery on NASH are due to weight loss alone or result from additional, weight-independent mechanisms, like in the case of T2DM. If the effect of surgery on inflammation, liver fibrosis and other mechanisms of cardiometabolic risk were found to be independent on weight reduction, there would be profound and far-reaching implications for both the treatment and the understanding of NASH, cardiovascular disease and obesity-related cancers. This project will investigate the hypothesis that, similarly to surgical control of diabetes, bariatric/metabolic surgery can also exert weight-independent effects on mechanisms of disease in NAFLD/NASH (i.e. influence on lowgrade inflammation and markers of fibrosis)

Conditions

Non-alcoholic Fatty Liver Disease (NAFLD); Non-Alcoholic Steato-Hepatitis (NASH)

Keywords

Metabolic Surgery; Bariatric Surgery; NASH; Diabetes; Obesity

Outcome Measures

Primary Outcomes (4)

• Assessment of liver inflammation and fibrosis

  Markers of liver injury in blood \[i.e. CK-18, tissue inhibitor of metalloproteinases (TIMP-1) amino-terminal pro-peptide of type III collagen (PIIINP), hyaluronic acid\].

  Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)

• Assessment of liver inflammation and fibrosis

  Serum adipokines \[i.e. adiponectin, visfatin, IL-6, TNFa\].

  Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)

• Assessment of liver inflammation and fibrosis

  FibroScan® score

  Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)

• Assessment of liver inflammation and fibrosis

  Fine Needle Aspiration of the liver to obtain a measurement of inflammatory cells in liver

  Change from baseline to 4-6 weeks (for the surgery group) and to 6 months (lifestyle intervention group)

Secondary Outcomes (4)

• Assessment of markers of cardiovascular disease in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)

  Changes from 0 to 30 and 60 minutes after meal consumption.

• Assessment of gut hormones in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)

  Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.

• Assessment of insulin sensitivity in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)

  Changes from -10 minutes to 0, 15, 30, 60, 90, 120 and 180 minutes after meal consumption.

• Assessment of bile acids in fasting and postprandial phase in response to a mixed meal test (MMT) in a subset of patients (total no.=18; 6 RYGB, 6 SG, 6 lifestyle intervention)

  Changes from 0 to 30 and 60 minutes after meal consumption.

Study Arms (2)

surgery group

EXPERIMENTAL

Fourteen patients who meet study criteria will be assigned to the study group and will undergo surgery; 7 RYGB and 7 SG, as planned for their standard care.

Procedure: Metabolic/Bariatric surgery

lifestyle and diet

ACTIVE COMPARATOR

Fourteen patients matched to the surgery group for age, gender, BMI, diabetes status, and NALFD score will undergo additional lifestyle interventions, dietary counselling and or meal replacement by a dietician aimed at inducing at least a 5-7% weight reduction, prior to their surgery (while on the waiting list for surgery).

Other: Lifestyle and Diet

Interventions

Metabolic/Bariatric surgery PROCEDURE

Patients will undergo surgery; 7 RYGB and 7 SG, as planned for their standard care.

surgery group

Lifestyle and Diet OTHER

Patients will be provided with a lifestyle interventions including dietary counselling choosing between a Low-Calorie Diet or a Meal Replacement Diet.

lifestyle and diet

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• BMI greater than 35 kg/m2 (or \>32.5. kg/m2 for patients of South Asian, Caribbean or Black ethnicities) with raised alanine transaminase (ALT), aspartate transaminase (AST) and a FibroScan® score \> 7.9 (indicating presence of NAFLD and high likelihood of NASH).

You may not qualify if:

• other causes of liver disease such as viral, alcoholic (alcohol consumption \>20 g/day for women or \>30 g/day for men),
• auto-immune disease
• use of certain medications that may interfere with outcome measures (i.e. corticosteroids, insulin and glycoprotein-1 (GLP-1) analogues).

Sponsors & Collaborators

• King's College London: lead

Study Sites (1)

King's College London

London, United Kingdom

RECRUITING

Related Publications (7)

• Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015 Jun 9;313(22):2263-73. doi: 10.1001/jama.2015.5370.

  PMID: 26057287 BACKGROUND

• Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ, Del Prato S, Ji L, Sadikot SM, Herman WH, Amiel SA, Kaplan LM, Taroncher-Oldenburg G, Cummings DE; Delegates of the 2nd Diabetes Surgery Summit. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. Diabetes Care. 2016 Jun;39(6):861-77. doi: 10.2337/dc16-0236.

  PMID: 27222544 BACKGROUND

• Jennings A, Hughes CA, Kumaravel B, Bachmann MO, Steel N, Capehorn M, Cheema K. Evaluation of a multidisciplinary Tier 3 weight management service for adults with morbid obesity, or obesity and comorbidities, based in primary care. Clin Obes. 2014 Oct;4(5):254-66. doi: 10.1111/cob.12066. Epub 2014 Jul 1.

  PMID: 25825858 BACKGROUND

• Pembroke T, Gallimore A, Godkin A. Tracking the kinetics of intrahepatic immune responses by repeated fine needle aspiration of the liver. J Immunol Methods. 2015 Sep;424:131-5. doi: 10.1016/j.jim.2015.04.011. Epub 2015 Apr 22.

  PMID: 25914090 BACKGROUND

• Pechlaner R, Tsimikas S, Yin X, Willeit P, Baig F, Santer P, Oberhollenzer F, Egger G, Witztum JL, Alexander VJ, Willeit J, Kiechl S, Mayr M. Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol. 2017 Feb 21;69(7):789-800. doi: 10.1016/j.jacc.2016.11.065.

  PMID: 28209220 BACKGROUND

• Halperin F, Ding SA, Simonson DC, Panosian J, Goebel-Fabbri A, Wewalka M, Hamdy O, Abrahamson M, Clancy K, Foster K, Lautz D, Vernon A, Goldfine AB. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014 Jul;149(7):716-26. doi: 10.1001/jamasurg.2014.514.

  PMID: 24899464 BACKGROUND

• Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, Raverdy V, Leteurtre E, Dharancy S, Louvet A, Romon M, Duhamel A, Pattou F, Mathurin P. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology. 2015 Aug;149(2):379-88; quiz e15-6. doi: 10.1053/j.gastro.2015.04.014. Epub 2015 Apr 25.

  PMID: 25917783 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Obesity

Interventions

Metabolic Networks and Pathways; Bariatric Surgery; Diet

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Metabolism; Bariatrics; Obesity Management; Therapeutics; Surgical Procedures, Operative; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Central Study Contacts

Rubino Francesco, MD

CONTACT

020 7848 5217; francesco.rubino@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study's population includes patients with severe obesity and non-alcoholic fatty liver disease who are eligible for bariatric surgery and are on the waiting list for either Roux en Y gastric bypass or sleeve gastrectomy at King's College Hospital. Main outcome measures will include several markers of inflammation and liver fibrosis assessed in plasma samples and Fine Needle Aspiration of the liver. Secondary outcome measures will include novel markers of cardiovascular risk, bile acids as well as standard markers of metabolic disease.

Study Record Dates

• First Submitted: September 20, 2019
• First Posted: February 24, 2020
• Study Start: February 13, 2020
• Primary Completion: March 30, 2021
• Study Completion: January 1, 2022
• Last Updated: March 5, 2020

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)